tbuckley/cabot-search huggingface dataset:
Elucidating the Genetic Landscape of Oral Leukoplakia to Predict Malignant Transformation
Authors: Leon J. Wils, Jos B. Poell, Arjen Brink, Ilkay Evren, Elisabeth R. Brouns, Jan G.A.M. de Visscher, Elisabeth Bloemena, Ruud H. Brakenhoff
Journal: Clinical Cancer Research (2022)

Abstract Purpose: Oral leukoplakia is the most common oral potentially malignant disorder with an annual malignant transformation rate of 1% to 5%. Consequently, oral leukoplakia patients have a 30% to 50% lifetime risk to develop oral squamous cell carcinoma. Although risk factors for malignant transformation of oral leukoplakia have been investigated, no definitive risk stratification model has been proposed. Next-generation sequencing can elucidate the genetic landscape of oral leukoplakia, which may be used to predict the risk for malignant transformation. Experimental Design: We investigated a retrospective cohort of 89 oral leukoplakia patients, and analyzed their oral leukoplakia lesions for the presence of genomic copy-number alterations and mutations in genes associated with oral squamous cell carcinoma. Results: In 25 of 89 (28%) patients, oral squamous cell carcinoma developed during follow-up. Seventy-nine of 89 (89%) oral leukoplakias harbored at least one genetic event. Copy-number alterations were present in 61 of 89 (69%) oral leukoplakias, most commonly gains of chromosome regions 8q24 (46%) and 20p11 (20%) and loss of 13q12 (19%). Mutations were present in 59 of 89 (66%) oral leukoplakias, most commonly in TP53 (28%), FAT1 (20%), and NOTCH1 (13%). Genetic data were combined with the presence of dysplasia to generate a prediction model, identifying three groups with a distinct risk for malignant transformation. Conclusions: We provide an extensive description of genetic alterations in oral leukoplakia and its relation to malignant transformation. On the basis of our data we provide a model for the prediction of malignant transformation of oral leukoplakia using dysplasia and genetic markers.
Meta-Analysis of Human Cancer Single-Cell RNA-Seq Datasets Using the IMMUcan Database
Authors: Jordi Camps, Floriane Noël, Robin Liechti, Lucile Massenet-Regad, Sidwell Rigade, Lou Götz, Caroline Hoffmann, Elise Amblard, Melissa Saichi, Mahmoud M. Ibrahim, Jack Pollard, Jasna Medvedovic, Helge G. Roider, Vassili Soumelis
Journal: Cancer Research (2022)

The development of single-cell RNA sequencing (scRNA-seq) technologies has greatly contributed to deciphering the tumor microenvironment (TME). An enormous amount of independent scRNA-seq studies have been published representing a valuable resource that provides opportunities for meta-analysis studies. However, the massive amount of biological information, the marked heterogeneity and variability between studies, and the technical challenges in processing heterogeneous datasets create major bottlenecks for the full exploitation of scRNA-seq data. We have developed IMMUcan scDB (https://immucanscdb.vital-it.ch), a fully integrated scRNA-seq database exclusively dedicated to human cancer and accessible to nonspecialists. IMMUcan scDB encompasses 144 datasets on 56 different cancer types, annotated in 50 fields containing precise clinical, technological, and biological information. A data processing pipeline was developed and organized in four steps: (i) data collection; (ii) data processing (quality control and sample integration); (iii) supervised cell annotation with a cell ontology classifier of the TME; and (iv) interface to analyze TME in a cancer type-specific or global manner. This framework was used to explore datasets across tumor locations in a gene-centric (CXCL13) and cell-centric (B cells) manner as well as to conduct meta-analysis studies such as ranking immune cell types and genes correlated to malignant transformation. This integrated, freely accessible, and user-friendly resource represents an unprecedented level of detailed annotation, offering vast possibilities for downstream exploitation of human cancer scRNA-seq data for discovery and validation studies.The IMMUcan scDB database is an accessible supportive tool to analyze and decipher tumor-associated single-cell RNA sequencing data, allowing researchers to maximally use this data to provide new insights into cancer biology.
Route of self-amplifying mRNA vaccination modulates the establishment of pulmonary resident memory CD8 and CD4 T cells
Authors: Marco Künzli, Stephen D. O’Flanagan, Madeleine LaRue, Poulami Talukder, Thamotharampillai Dileepan, J. Michael Stolley, Andrew G. Soerens, Clare F. Quarnstrom, Sathi Wijeyesinghe, Yanqi Ye, Justine S. McPartlan, Jason S. Mitchell, Christian W. Mandl, Richard Vile, Marc K. Jenkins, Rafi Ahmed, Vaiva Vezys, Jasdave S. Chahal, David Masopust
Journal: Science Immunology (2022)

Respiratory tract resident memory T cells (T
IL-2 is inactivated by the acidic pH environment of tumors enabling engineering of a pH-selective mutein
Authors: Silvia Gaggero, Jonathan Martinez-Fabregas, Adeline Cozzani, Paul K. Fyfe, Malo Leprohon, Jie Yang, F. Emil Thomasen, Hauke Winkelmann, Romain Magnez, Alberto G. Conti, Stephan Wilmes, Elizabeth Pohler, Manuel van Gijsel Bonnello, Xavier Thuru, Bruno Quesnel, Fabrice Soncin, Jacob Piehler, Kresten Lindorff-Larsen, Rahul Roychoudhuri, Ignacio Moraga, Suman Mitra
Journal: Science Immunology (2022)

Cytokines interact with their receptors in the extracellular space to control immune responses. How the physicochemical properties of the extracellular space influence cytokine signaling is incompletely elucidated. Here, we show that the activity of interleukin-2 (IL-2), a cytokine critical to T cell immunity, is profoundly affected by pH, limiting IL-2 signaling within the acidic environment of tumors. Generation of lactic acid by tumors limits STAT5 activation, effector differentiation, and antitumor immunity by CD8
A comparison of the International Consensus and 5th World Health Organization classifications of mature B-cell lymphomas
Authors: Brunangelo Falini, Giovanni Martino, Stefano Lazzi
Journal: Leukemia (2022)

Abstract Several editions of the World Health Organization (WHO) classifications of lympho-hemopoietic neoplasms in 2001, 2008 and 2017 served as the international standard for diagnosis. Since the 4th WHO edition, here referred as WHO-HAEM4, significant clinico-pathological, immunophenotypic and molecular advances have been made in the field of lymphomas, contributing to refining diagnostic criteria of several diseases, to upgrade entities previously defined as provisional and to identify new entities. This process has resulted in two recent classifying proposals of lymphoid neoplasms, the International Consensus Classification (ICC) and the 5th edition of the WHO classification (WHO-HAEM5). In this paper, we review and compare the two classifications in terms of diagnostic criteria and entity definition, with focus on mature B-cell neoplasms. The main aim is to provide a tool to facilitate the work of pathologists, hematologists and researchers involved in the diagnosis and treatment of lymphomas.
Transient regulation of RNA methylation in human hematopoietic stem cells promotes their homing and engraftment
Authors: Xuepeng Wang, Scott Cooper, Hal E. Broxmeyer, Reuben Kapur
Journal: Leukemia (2022)

Enhancing the efficiency of hematopoietic stem cell (HSC) homing and engraftment is critical for cord blood (CB) hematopoietic cell transplantation (HCT). Recent studies indicate that N6-methyladenosine (m6A) modulates the expression of mRNAs that are critical for stem cell function by influencing their stability. Here, we demonstrate that inhibition of RNA decay by regulation of RNA methylation, enhances the expression of the homing receptor chemokine C-X-C receptor-4 (CXCR4) in HSCs. We show that YTH N6-methyladenosine RNA binding protein 2 (YTHDF2), a m6A reader and FTO α-ketoglutarate dependent dioxygenase (FTO), a m6A eraser play an opposite role in this process. Through screening, we identified several FDA-approved compounds that regulate the expression of YTHDF2 and FTO in CB CD34+ cells. We show that transient downregulation of YTHDF2 or activation of FTO by using these compounds inhibits CXCR4 decay in CB HSCs and promotes their homing and engraftment. Our results demonstrate a novel regulation strategy to enhance the function of CB HSCs and provide a translational approach to enhance the clinical efficacy of HCT.
Axatilimab for Chronic Graft-Versus-Host Disease After Failure of at Least Two Prior Systemic Therapies: Results of a Phase I/II Study
Authors: Carrie L. Kitko, Mukta Arora, Zachariah DeFilipp, Mohammad Abu Zaid, Antonio Di Stasi, Vedran Radojcic, Courtney B. Betts, Lisa M. Coussens, Michael L. Meyers, Hope Qamoos, Peter Ordentlich, Vinit Kumar, Christine Quaranto, Aaron Schmitt, Yu Gu, Bruce R. Blazar, Trent P. Wang, Amandeep Salhotra, Iskra Pusic, Madan Jagasia, Stephanie J. Lee
Journal: Journal of Clinical Oncology (2022)

Chronic graft-versus-host disease (cGVHD) remains the major cause of late morbidity after allogeneic hematopoietic cell transplantation. Colony-stimulating factor 1 receptor (CSF-1R)-dependent macrophages promote cGVHD fibrosis, and their elimination in preclinical studies ameliorated cGVHD. Axatilimab is a humanized monoclonal antibody that inhibits CSF-1R signaling and restrains macrophage development.
Ipilimumab plus nivolumab in avelumab-refractory Merkel cell carcinoma: a multicenter study of the prospective skin cancer registry ADOREG
Authors: Valerie Glutsch, Patrick Schummer, Hermann Kneitz, Anja Gesierich, Matthias Goebeler, Detlef Klein, Christian Posch, Christoffer Gebhardt, Sebastian Haferkamp, Lisa Zimmer, Jürgen C Becker, Ulrike Leiter, Michael Weichenthal, Dirk Schadendorf, Selma Ugurel, Bastian Schilling
Journal: Journal for ImmunoTherapy of Cancer (2022)

Merkel cell carcinoma is a rare, highly aggressive skin cancer with neuroendocrine differentiation. Immune checkpoint inhibition has significantly improved treatment outcomes in metastatic disease with response rates to programmed cell death protein 1/programmed cell death 1 ligand 1 (PD-1/PD-L1) inhibition of up to 62%. However, primary and secondary resistance to PD-1/PD-L1 inhibition remains a so far unsolved clinical challenge since effective and safe treatment options for these patients are lacking. Fourteen patients with advanced (non-resectable stage III or stage IV, Union international contre le cancer 2017) Merkel cell carcinoma with primary resistance to the PD-L1 inhibitor avelumab receiving subsequent therapy (second or later line) with ipilimumab plus nivolumab (IPI/NIVO) were identified in the prospective multicenter skin cancer registry ADOREG. Five of these 14 patients were reported previously and were included in this analysis with additional follow-up. Overall response rate, progression-free survival (PFS), overall survival (OS) and adverse events were analyzed. All 14 patients received avelumab as first-line treatment. Thereof, 12 patients had shown primary resistance with progressive disease in the first tumor assessment, while two patients had initially experienced a short-lived stabilization (stable disease). Six patients had at least one systemic treatment in between avelumab and IPI/NIVO. In total, 7 patients responded to IPI/NIVO (overall response rate 50%), and response was ongoing in 4 responders at last follow-up. After a median follow-up of 18.85 months, median PFS was 5.07 months (95% CI 2.43—not available (NA)), and median OS was not reached. PFS rates at 12 months and 24 months were 42.9% and 26.8 %, respectively. The OS rate at 36 months was 64.3%. Only 3 (21%) patients did not receive all 4 cycles of IPI/NIVO due to immune-related adverse events. In this multicenter evaluation, we observed high response rates, a durable benefit and promising OS rates after treatment with later-line combined IPI/NIVO. In conclusion, our patient cohort supports our prior findings with an encouraging activity of second-line or later-line IPI/NIVO in patients with anti-PD-L1-refractory Merkel cell carcinoma.
Nivolumab after selective internal radiation therapy for the treatment of hepatocellular carcinoma: a phase 2, single-arm study
Authors: Manuel de la Torre-Aláez, Ana Matilla, Maria Varela, Mercedes Iñarrairaegui, Maria Reig, Jose Luis Lledó, Juan Ignacio Arenas, Sara Lorente, Milagros Testillano, Laura Márquez, Leonardo Da Fonseca, Josepmaria Argemí, Carlos Gómez-Martin, Macarena Rodriguez-Fraile, Jose I Bilbao, Bruno Sangro
Journal: Journal for ImmunoTherapy of Cancer (2022)

To evaluate the safety and efficacy of selective internal radiation therapy (SIRT) in combination with a PD-1 inhibitor in patients with unresectable hepatocellular carcinoma (uHCC) and liver-only disease ineligible for chemoembolization.NASIR-HCC is a single-arm, multicenter, open-label, phase 2 trial that recruited from 2017 to 2019 patients who were naïve to immunotherapy and had tumors in the BCLC B2 substage (single or multiple tumors beyond the up-to-7 rule), or unilobar tumors with segmental or lobar portal vein invasion (PVI); no extrahepatic spread; and preserved liver function. Patients received SIRT followed 3 weeks later by nivolumab (240 mg every 2 weeks) for up to 24 doses or until disease progression or unacceptable toxicity. Safety was the primary endpoint. Secondary objectives included objective response rate (ORR), time to progression (TTP), and overall survival (OS).42 patients received SIRT (31 BCLC-B2, 11 with PVI) and were followed for a median of 22.2 months. 27 patients discontinued and 1 never received Nivolumab. 41 patients had any-grade adverse events (AE) and 21 had serious AEs (SAE). Treatment-related AEs and SAEs grade 3-4 occurred in 8 and 5 patients, respectively. Using RECIST 1.1 criteria, ORR reported by investigators was 41.5% (95% CI 26.3% to 57.9%). Four patients were downstaged to partial hepatectomy. Median TTP was 8.8 months (95% CI 7.0 to 10.5) and median OS was 20.9 months (95% CI 17.7 to 24.1).The combination of SIRT and nivolumab has shown an acceptable safety profile and signs of antitumor activity in the treatment of patients with uHCC that were fit for SIRT.NCT03380130.
Phase II clinical and immune correlate study of adjuvant nivolumab plus ipilimumab for high-risk resected melanoma
Authors: Nikhil I Khushalani, Melinda Vassallo, Judith D Goldberg, Zeynep Eroglu, Younchul Kim, Biwei Cao, Robert Ferguson, Kelsey R Monson, Tomas Kirchhoff, Carol M Amato, Paulo Burke, Ann Strange, Emily Monk, Geoffrey Thomas Gibney, Ragini Kudchadkar, Joseph Markowitz, Andrew S Brohl, Anna Pavlick, Alison Richards, David M Woods, Jeffrey Weber
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background Adjuvant therapy for high-risk resected melanoma with programmed cell-death 1 blockade results in a median relapse-free survival (RFS) of 5 years. The addition of low dose ipilimumab (IPI) to a regimen of adjuvant nivolumab (NIVO) in CheckMate-915 did not result in increased RFS. A pilot phase II adjuvant study of either standard dose or low dose IPI with NIVO was conducted at two centers to evaluate RFS with correlative biomarker studies. Methods Patients with resected stages IIIB/IIIC/IV melanoma received either IPI 3 mg/kg and NIVO 1 mg/kg (cohort 4) or IPI 1 mg/kg and NIVO 3 mg/kg (cohorts 5 and 6) induction therapy every 3 weeks for 12 weeks, followed by maintenance NIVO. In an amalgamated subset of patients across cohorts, peripheral T cells at baseline and on-treatment were assessed by flow cytometry and RNA sequencing for exploratory biomarkers. Results High rates of grade 3–4 adverse events precluded completion of induction therapy in 50%, 35% and 7% of the patients in cohorts 4, 5 and 6, respectively. At a median of 63.9 months of follow-up, 16/56 patients (29%) relapsed. For all patients, at 5 years, RFS was 71% (95% CI: 60 to 84), and overall survival was 94% (95% CI: 88 to 100). Expansion of CD3+CD4+CD38+CD127−GARP− T cells, an on-treatment increase in CD39 expression in CD8+ T cells, and T-cell expression of phosphorylated signal-transducer-and-activator-of-transcription (STAT)2 and STAT5 were associated with relapse. Conclusions Adjuvant IPI/NIVO at the induction doses used resulted in promising relapse-free and overall survival, although with a high rate of grade 3–4 adverse events. Biomarker analyses highlight an association of ectoenzyme-expressing T cells and STAT signaling pathways with relapse, warranting future validation. Trial registration number NCT01176474 and NCT02970981 .
Enhanced efficacy of direct immunochemotherapy for hepatic cancer with image-guided intratumoral radiofrequency hyperthermia
Authors: Xuefeng Kan, Guanhui Zhou, Feng Zhang, Hongxiu Ji, David S Shin, Wayne Monsky, Chuansheng Zheng, Xiaoming Yang
Journal: Journal for ImmunoTherapy of Cancer (2022)

It is still a challenge to prevent tumor recurrence post radiofrequency ablation (RFA) of medium-to-large hepatocellular carcinomas (HCC). Immunochemotherapy, a combination of immunotherapy with chemotherapy, has demonstrated a great potential in augmenting the treatment efficacy for some malignancies. In this study, we validated the feasibility of using radiofrequency hyperthermia (RFH)-enhanced intratumoral immunochemotherapy of LTX-315 with liposomal doxorubicin for rat orthotopic HCC.
Rechallenge of immune checkpoint inhibitors in a case with adverse events inducing myasthenia gravis
Authors: Wen Gao, Lingxiang Wu, Shidai Jin, Jun Li, Xinyin Liu, Jiali Xu, Wei Zhang, Qixing Gong, Chunxiao Sun, Wei Wang, Zidun Wang, Yang W Shao, Jiani C Yin, Lu Shen, Liang Chen, Qianghu Wang, Renhua Guo
Journal: Journal for ImmunoTherapy of Cancer (2022)

The mechanism(s) of immune checkpoint inhibitor (ICI)-induced myasthenia gravis (MG), an immune-related adverse event (irAE) that is fatal and limits subsequent ICI use, remain unexplored. Here, through comparative genomic analysis, we identified a pathogenic p.S467C germline variant in SLC22A5 in a thymoma case with ICI-induced MG, which was found to be associated with fatty acid oxidation through its regulation on L-carnitine levels. Remarkably, ICI rechallenge with L-carnitine pretreatment led to durable response without MG-related symptoms. Thus, we provide the first clinical evidence of genetic test-directed irAE management, which integrates individualized ICI treatment into the evolving paradigm of cancer management.
Monoclonal Antibody‐Guided Tumor‐Targeted Hollow Virus‐Like Cerium Oxide with Oxygen Self‐Supply for Intensifying Photodynamic Therapy
Authors: Mengqi Li, Jiajing Liu, Xian Luo, Zhiyu Zhao, Shengyu Wang, Zongjunlin Liu, Tingting Li, Dong Yang, Yang Li, Peiyuan Wang, Fanghong Luo, Jianghua Yan
Journal: Advanced Healthcare Materials (2022)

The hypoxic character of tumors and the poor targeting ability of photosensitizers often limit the efficacy of photodynamic therapy (PDT). In recent years, the discovery of metal nanoenzymes and nanocarriers has improved PDT. Thereby, to improve the effective utilization of photosensitizers and oxygen (O2 ) in tumors, herein, a nanosystem (LS-HB@HvCeO2 -NRP1 mAb, LHCN1) is reported, in which a hollow virus-like cerium oxide (HvCeO2 ) is surface-decorated with tumor-targeting neuropilin-1 monoclonal antibody (NRP1 mAb), and loaded with a photosensitizer (chlorin e6-C-15-ethyl ester, LS-HB). In vitro and in vivo experiments demonstrate that LHCN1 can efficiently accumulate within the tumor sites via the targeting guidance of NRP1 mAb and is then rapidly endocytosed into cells. Furthermore, HvCeO2 with catalase-mimetic activity can decompose the endogenous hydrogen peroxide (H2 O2 ) to promote O2 via the valence transformation between Ce4+ and Ce3+ , relieving tumor hypoxia and improving the PDT efficacy. Upon near-infrared laser irradiation, LS-HB produces large amounts of cytotoxic reactive oxygen species. Moreover, LHCN1 is used in fluorescence/photoacoustic multimodal imaging for in vivo drug localization, and its use in PDT evidently helps inhibit tumor growth with no apparent toxicity to normal tissues. Thus, LHCN1 may provide a promising strategy for precise tumor-specific diagnosis and treatment.
Parenteral BCG vaccine induces lung-resident memory macrophages and trained immunity via the gut–lung axis
Authors: Mangalakumari Jeyanathan, Maryam Vaseghi-Shanjani, Sam Afkhami, Jensine A. Grondin, Alisha Kang, Michael R. D’Agostino, Yushi Yao, Shreya Jain, Anna Zganiacz, Zachary Kroezen, Meera Shanmuganathan, Ramandeep Singh, Anna Dvorkin-Gheva, Philip Britz-McKibbin, Waliul I. Khan, Zhou Xing
Journal: Nature Immunology (2022)

Aside from centrally induced trained immunity in the bone marrow (BM) and peripheral blood by parenteral vaccination or infection, evidence indicates that mucosal-resident innate immune memory can develop via a local inflammatory pathway following mucosal exposure. However, whether mucosal-resident innate memory results from integrating distally generated immunological signals following parenteral vaccination/infection is unclear. Here we show that subcutaneous Bacillus Calmette-Guérin (BCG) vaccination can induce memory alveolar macrophages (AMs) and trained immunity in the lung. Although parenteral BCG vaccination trains BM progenitors and circulating monocytes, induction of memory AMs is independent of circulating monocytes. Rather, parenteral BCG vaccination, via mycobacterial dissemination, causes a time-dependent alteration in the intestinal microbiome, barrier function and microbial metabolites, and subsequent changes in circulating and lung metabolites, leading to the induction of memory macrophages and trained immunity in the lung. These data identify an intestinal microbiota-mediated pathway for innate immune memory development at distal mucosal tissues and have implications for the development of next-generation vaccine strategies against respiratory pathogens.
Dietary ketone body–escalated histone acetylation in megakaryocytes alleviates chemotherapy-induced thrombocytopenia
Authors: Sisi Xie, Chenyu Jiang, Meng Wu, Ying Ye, Biying Wu, Xiaoting Sun, Xue Lv, Ruibo Chen, Wen Yu, Qi Sun, Yuting Wu, Rongliang Que, Huilan Li, Ling Yang, Wen Liu, Ji Zuo, Lasse D. Jensen, Guichun Huang, Yihai Cao, Yunlong Yang
Journal: Science Translational Medicine (2022)

Chemotherapy-induced thrombocytopenia (CIT) is a severe complication in patients with cancer that can lead to impaired therapeutic outcome and survival. Clinically, therapeutic options for CIT are limited by severe adverse effects and high economic burdens. Here, we demonstrate that ketogenic diets alleviate CIT in both animals and humans without causing thrombocytosis. Mechanistically, ketogenic diet-induced circulating β-hydroxybutyrate (β-OHB) increased histone H3 acetylation in bone marrow megakaryocytes. Gain- and loss-of-function experiments revealed a distinct role of 3-β-hydroxybutyrate dehydrogenase (BDH)-mediated ketone body metabolism in promoting histone acetylation, which promoted the transcription of platelet biogenesis genes and induced thrombocytopoiesis. Genetic depletion of the megakaryocyte-specific ketone body transporter monocarboxylate transporter 1 (MCT1) or pharmacological targeting of MCT1 blocked β-OHB-induced thrombocytopoiesis in mice. A ketogenesis-promoting diet alleviated CIT in mouse models. Moreover, a ketogenic diet modestly increased platelet counts without causing thrombocytosis in healthy volunteers, and a ketogenic lifestyle inversely correlated with CIT in patients with cancer. Together, we provide mechanistic insights into a ketone body-MCT1-BDH-histone acetylation-platelet biogenesis axis in megakaryocytes and propose a nontoxic, low-cost dietary intervention for combating CIT.